Mammalian cells respond to extracellular stimulation as a result of the activation of a signal cascade via a mitogen activated protein kinase (MAPK) family member. There are three kinds of MAPK, c-Jun N-terminal kinase (JNK) (alternative name: stress activated protein kinase (SAPK)), p38MAP kinase and extracellular signal regulated kinase (ERK), and they are activated by various signals such as growth factors, cytokines, ultraviolet radiation, stress inducers and the like. Since MAPK is a serine/threonine kinase, it is activated by phosphorylation of both threonine and tyrosine of the Thr-X-Tyr sequence in the activation loop. MAPK controls expression of a particular gene by phosphorylation-activation of various transcription factors, and mediates a specific response to an extracellular stimulation.
There have been identified three genes of JNK: jnk1, jnk2 and jnk3, and at least 10 kinds of isoforms are present in mammals (EMBO Journal, vol. 15, pp. 2760-2770 (1996)). While Jnk1 and jnk2 express in many tissues, jnk3 specifically expresses in the brain. Thus, JNK3 has a potential to be particularly involved in nervous function. The JNK signal transduction system of stress response MAP kinase family system is activated by changes in osmotic pressure, DNA damage, anisomycine, heat shock, ultraviolet radiation, ischemia, inflammatory cytokines and the like and various stress stimulations relating to apoptosis induction, it is considered to constitute a major intracellular information transduction path responsible for stress response (Biochemica et Biophysica Acta, vol. 1333, pp. F85-F104 (1997)). The activated JNK activates various transcription factors such as c-Jun, ATF-2, Elk1, p53, cell death domain protein (DENN) and the like and cell death (apoptosis) signal, thereby suppressing transcription activity of particular gene, or induces apoptosis to respond to environmental changes such as various stresses and the like (Proceedings of the National Academy of Sciences of the United States of America, vol. 95, pp. 2586-2591 (1998)). Chronic activation of JNK is seen in various clinical conditions and diseases such as cancer, cell death, allergy, asthma, heart disease, autoimmune disease, ischemic disease, inflammation, neurodegenerative disease and the like, which suggests close involvement of activation of JNK in the onset and aggravation of these diseases. [In the present specification, these clinical conditions or diseases, in which such activation of JNK is involved, are referred to as a “JNK-related clinical condition or disease”.]
As for the relationship between JNK and various JNK-related clinical conditions or diseases, for example, it is known that JNK is activated by dilation stimulation or ischemia and transduces stress signals in cardiac myocytes. JNK is also activated by catecholamine, angiotensin II or endothelin and controls expression of factors (BNP/ANP, TNF-α, TGF-β, MMPs and the like) involved in cardiac hypertrophy and fibrosis (Journal of Biological Chemistry, vol. 270, pp. 29710-29717, FASEB Journal, vol. 10, pp. 631-636 (1996), Circulation Research, vol. 80, pp. 139-146 (1997)). Recently, it has been reported that JNK activity in the hearts of cardiac failure patients increases after the onset of myocardial infarction and an MKK7 (JNK selective kinase) heart excessive expression mouse develops cardiac failure, which suggests involvement of JNK in the progression process of cardiac failure (Journal of Molecular and Cellular Cardiology, vol. 31, pp. 1429-1434 (1999)). In addition, it has been reported that JNK inhibition by dominant negative MKK7 suppresses cardiac hypertrophy without affecting the blood pressure in a pressure burden cardiac hypertrophy model (Journal of Clinical Investigation, vol. 104, pp. 391-398 (1999)). Furthermore, it has been reported that dominant negative MKK7 lowers JNK activity and suppress cardiac myocyte death in an ischemia-reperfusion model. Therefore, JNK inhibitors are possibly effective for the treatment of ischemic heart disease, cardiac failure, post-myocardial infarction and cardiac hypertrophy.
By activating the IL-2 promoter, JNK plays a key role in the T-Cell activation. From a recent experiment using knock out mouse, JNK is reported to also play a key role in the differentiation of the Th1 and Th2 cells. Therefore, JNK inhibitors are possibly effective for the treatment of pathologic immunity disease (Journal of Immunology, vol. 162, pp. 3176-3187, 1999, European Journal of Immunology, vol. 28, pp. 3867-3877, 1998, Journal of Experimental Medicine, vol. 186, pp. 941-953, 1997, European Journal of Immunology, vol. 26, pp. 989-994, 1996, Current Biology, vol. 9, pp. 116-125, 1999).
It is reported that since JNK is activated in synovial cell in rheumatics and JNK controls the expression of MMP gene in IL-1-stimulated synovial cell, JNK is deeply involved in the articular destruction of rheumatics (Journal of Clinical Investigation, vol. 108, pp. 73-81, 2001). This suggests the possibility of JNK inhibitor to be effective for the treatment of rheumatic diseases.
In view of resistance to apoptosis of nerve cells due to the administration of a large amount of kainic acid in JNK3 knock out mouse, JNK3 plays an important role in the expression of glutamate type neurotoxicity (Nature, vol. 389, pp. 865-870, 1997). In addition, JNK3 is activated in nerve cells in the state of low oxygen or ischemia to cause apoptosis. From these, a JNK inhibitor is possibly effective for the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's syndrome and Huntington's chorea or ischemia or hemorrhagic cerebral apoplexy.
Furthermore, from an experiment using a JNK1 deletion mouse, JNK is reported to be an important mediator involved in obesity and insulin resistance (Nature, vol. 420, pp. 333-336 (2002)).
As a compound having a JNK inhibitory action, for example, indolinone derivatives are disclosed in WO99/35906, WO99/35909 and WO99/35921, uracil derivatives are disclosed in WO00/75118, isoxazole derivatives are disclosed in WO01/12621, thiophenesulfonamide derivatives are disclosed in WO01/23378, WO01/23379 and WO01/23382, pyrazoloanthrone derivatives are disclosed in WO01/12609 and pyrimidylimidazole derivatives are disclosed in WO01/91749. However, an isoquinolinone derivative having a JNK inhibitory action has not been reported.
On the other hand, isoquinolinone derivatives are disclosed in JP-A-10-298164, JP-A-2000-72675, JP-A-2000-72751, JP-A-5-132463, JP-A-6-321906, JP-A-7-010844, JP-A-7-076573, WO02/062764 and the like.